US 12,440,486 B2
RBP4 antagonists for treatment and prevention of non-alcoholic fatty liver disease and gout
Konstantin Petrukhin, New Windsor, NY (US); Boglarka Racz, Brooklyn, NY (US); and Andras Varadi, Brooklyn, NY (US)
Assigned to THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, New York, NY (US)
Appl. No. 17/261,851
Filed by The Trustees of Columbia University in the City of New York, New York, NY (US)
PCT Filed Aug. 1, 2019, PCT No. PCT/US2019/044754
§ 371(c)(1), (2) Date Jan. 20, 2021,
PCT Pub. No. WO2020/028723, PCT Pub. Date Feb. 6, 2020.
Claims priority of provisional application 62/713,288, filed on Aug. 1, 2018.
Prior Publication US 2023/0241049 A1, Aug. 3, 2023
Int. Cl. A61K 31/4545 (2006.01); A61K 31/506 (2006.01); A61P 1/16 (2006.01); A61P 19/06 (2006.01)
CPC A61K 31/4545 (2013.01) [A61K 31/506 (2013.01); A61P 1/16 (2018.01); A61P 19/06 (2018.01)] 22 Claims
OG exemplary drawing
 
1. A method for treating gout in a subject afflicted therewith comprising administering to the subject a pharmaceutical composition comprising an amount of a compound effective to treat the subject, thereby treating the subject, wherein compound has the structure

OG Complex Work Unit Chemistry
wherein L is a linking group having the structure:

OG Complex Work Unit Chemistry
and Z is a group having the structure:

OG Complex Work Unit Chemistry
wherein
R1, R2, R3, R4, and R5 are each independently H, halogen, CF3 or C1-C4 alkyl, aryl or heteroaryl;
R6 is H, OH, or halogen or absent;
ψ is absent or present, and when present is a bond;
B is a substituted or unsubstituted heterobicycle, pyridazine, pyrazole, pyrazine, thiadiazole, or triazole, wherein the heterobicycle is other than chloro substituted indole; and
the pyrazole, when substituted, is substituted with other than trifluoromethyl;
B′ is a substituted or unsubstituted phenyl, pyridine, pyrimidine, benzyl, pyrrolidine, sulfolane, oxetane, CO2H or (C1-C4 alkyl)-CO2H,
wherein the substituted phenyl is substituted with other than trifluoromethyl or 3-(methyl carboxylate), the substituted pyridine is substituted with other than trifluoromethyl and the substituted pyrrolidine is substituted with other than hydroxamic acid, and
the substituted or unsubstituted pyrrolidine is bound to the carbonyl through a carbon-carbon bond;
A is absent or present, and when present is

OG Complex Work Unit Chemistry
B1 is substituted or unsubstituted monocycle, bicycle, heteromonocycle, heterobicycle, benzyl, CO2H or (C1-C4 alkyl)-CO2H,
wherein when B1 is CO2H, then A is present
and is

OG Complex Work Unit Chemistry
R7 is alkyl;
X is N or CR8, wherein R8 is H, OH, or halogen;
B2 has the structure:

OG Complex Work Unit Chemistry
wherein
α and β are each a bond that is present or absent;
X1 is N, NH or NR99,
wherein R99 is alkyl, alkenyl or alkynyl;
X2 is C or N;
X3 is CH or N;
R9, R10 and R11 are each, independently, H, halogen, alkyl, alkenyl, alkynyl, alkyl-OH, alkyl-NH2, alkyl-OAc alkyl-O(CO)-alkyl, alkyl-O-alkyl, haloalkyl, cycloalkyl, O-alkyl, NH-alkyl, C(O)OH, C(O)—NH2, C(O)—N(CH3)2, C(O)—NHCH3, NHC(O)—N(CH3)2, CN or CF3,
wherein
X1, X2 and X3 are each N, α is present and β is absent; or
X1, X2 and X3 are each N, α is present and β is absent; or
X1, X2 and X3 are each N, α is present and β is absent; or
X1 is NH or NR99, X2 is C, X3 is N, α is absent and β is present, wherein
when X1 is NH, X2 is C, X3 is N, α is absent and β is present, then one of R9, R10 and R11 is other than H,
or B2 has the structure:

OG Complex Work Unit Chemistry
wherein
R12, R13 and R14 are each, independently, H, halogen, alkyl, alkenyl, alkynyl alkyl-OH, alkyl-NH2, alkyl-OAc, alkyl-O(CO)-alkyl, alkyl-O-alkyl, haloalkyl, cycloalkyl, O-alkyl, NH-alkyl, C(O)OH, C(O)—NH2, C(O)—N(CH3)2, C(O)—NHCH3, NHC(O)—N(CH3)2, CN or CF3, or a pharmaceutically acceptable salt thereof.